In recent years, it has become clear that angiogenesis, the growth of new capillary blood vessels from pre-existing vasculature, is important not only in physiological processes such as embryonic development, the female reproductive cycle, wound healing, and organ and tissue regeneration, but also in pathological processes such as tumor progression and metastasis1. Angiogenesis is now recognized as a critical process for all malignancies2,3. As a result, the microvascular endothelial cell, which is recruited by tumors, has become an important second target in cancer therapy. It is widely accepted that the endothelial cell target, unlike the tumor cells themselves is genetically stable1. Antiangiogenic agents have recently emerged as a new class of drugs; however, the optimal means to use these agents alone or in combination with drug delivery systems and with conventional chemotherapy have not yet been fully elucidated.
The hypothesis that tumor growth is angiogenesis-dependent is supported by biological and pharmacological evidence4 and confirmed by genetic evidence3,5-7. Both types of evidence provide a scientific basis for current clinical trials of angiogenesis inhibitors. Increased tumor angiogenesis4,8 and elevated levels of proangiogenic factors such as vascular endothelial growth factor (VEGF/VPF)8,9, basic fibroblast growth factor (bFGF)8, and interleukin-8 (IL-8)10 correlate with decreased survival and increased risk of relapse in studies of patients with malignant solid tumors. The importance of angiogenesis is further supported by the observation that antiangiogenic agents inhibit tumor growth in a variety of animal models.
In the U.S. there are currently more than 30 angiogenesis inhibitors in various clinical trials for late-stage cancer. One of these angiogenesis inhibitors, O-(chloracetyl-carbamoyl) fumagillol (TNP-470), is a low molecular weight synthetic analogue of fumagillin11, a compound secreted by the fungus Aspergillus fumigatus fresenius. TNP-470 is a potent endothelial inhibitor in vitro12. Recently, TNP-470 has been tested as a potential new anticancer agent. In animal models, TNP-470 has the broadest anticancer spectrum of any known agent4,13. TNP-470 inhibited the growth of murine tumors up to 91%, human tumors up to 100% and metastatic tumors up to 100% in mice (reviewed in ref. 13) In most studies, mice were treated at the same optimal dose of 30 mg/kg subcutaneously every other day. In clinical trials TNP-470 has shown evidence of antitumor activity when used as a single agent, with a number of objective responses reported with relapsed and refractory malignancies14-16. It has also shown promise when used in combination with conventional chemotherapy17,18. However, many patients experience neurotoxicity (malaise, rare seizures, asthenia, anxiety and dysphoria)16,17,19,20 at doses where antitumor activity has been seen. Because of dose-limiting neurotoxicity, TNP-470 has been tested using multiple dosing regimens, but these attempts to limit its toxicity have been unsuccessful. With few exceptions, weight loss or failure to gain weight was observed in animals receiving TNP-47021, and two reports noted a decrease in splenic weight22,23. Therefore, modifications of TNP-470 that can retain or increase its activity while reducing its toxicity are highly desirable.